DK2490675T3 - Pharmaceutical compositions with sevelamer - Google Patents
Pharmaceutical compositions with sevelamer Download PDFInfo
- Publication number
- DK2490675T3 DK2490675T3 DK09741235.7T DK09741235T DK2490675T3 DK 2490675 T3 DK2490675 T3 DK 2490675T3 DK 09741235 T DK09741235 T DK 09741235T DK 2490675 T3 DK2490675 T3 DK 2490675T3
- Authority
- DK
- Denmark
- Prior art keywords
- tablet
- sevelamer
- tablets
- coating
- sevelamer carbonate
- Prior art date
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- ZNSIZMQNQCNRBW-UHFFFAOYSA-N sevelamer Chemical compound NCC=C.ClCC1CO1 ZNSIZMQNQCNRBW-UHFFFAOYSA-N 0.000 title description 37
- 229960003693 sevelamer Drugs 0.000 title description 33
- 239000008194 pharmaceutical composition Substances 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims description 57
- PADGNZFOVSZIKZ-UHFFFAOYSA-N 2-(chloromethyl)oxirane;hydrogen carbonate;prop-2-enylazanium Chemical compound NCC=C.OC(O)=O.ClCC1CO1 PADGNZFOVSZIKZ-UHFFFAOYSA-N 0.000 claims description 50
- 229960005441 sevelamer carbonate Drugs 0.000 claims description 50
- 238000000576 coating method Methods 0.000 claims description 49
- 239000011248 coating agent Substances 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 26
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 25
- 239000011230 binding agent Substances 0.000 claims description 14
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 12
- 229960001021 lactose monohydrate Drugs 0.000 claims description 12
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- 229920002678 cellulose Polymers 0.000 claims description 10
- 239000001913 cellulose Substances 0.000 claims description 10
- 238000007907 direct compression Methods 0.000 claims description 10
- 239000007884 disintegrant Substances 0.000 claims description 10
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 9
- 239000007888 film coating Substances 0.000 claims description 8
- 238000009501 film coating Methods 0.000 claims description 8
- 239000008213 purified water Substances 0.000 claims description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 208000020832 chronic kidney disease Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000004094 surface-active agent Substances 0.000 claims description 5
- 150000001450 anions Chemical class 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 210000002966 serum Anatomy 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 2
- 229920001577 copolymer Polymers 0.000 claims 2
- 230000001105 regulatory effect Effects 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 94
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 16
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 15
- 238000009472 formulation Methods 0.000 description 15
- 229960001375 lactose Drugs 0.000 description 15
- 239000008101 lactose Substances 0.000 description 15
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 11
- 102000006335 Phosphate-Binding Proteins Human genes 0.000 description 11
- 108010058514 Phosphate-Binding Proteins Proteins 0.000 description 11
- 229930195725 Mannitol Natural products 0.000 description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 10
- 239000000594 mannitol Substances 0.000 description 10
- 235000010355 mannitol Nutrition 0.000 description 10
- 239000000314 lubricant Substances 0.000 description 9
- 235000010980 cellulose Nutrition 0.000 description 8
- 238000012937 correction Methods 0.000 description 8
- 239000003085 diluting agent Substances 0.000 description 8
- 229920000578 graft copolymer Polymers 0.000 description 8
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 8
- 229920002554 vinyl polymer Polymers 0.000 description 8
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 7
- 238000009736 wetting Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- 239000007916 tablet composition Substances 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 229940047681 renvela Drugs 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 239000007941 film coated tablet Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 208000017169 kidney disease Diseases 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- -1 many other polyols Chemical compound 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 2
- SERLAGPUMNYUCK-DCUALPFSSA-N 1-O-alpha-D-glucopyranosyl-D-mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SERLAGPUMNYUCK-DCUALPFSSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- KHNXRSIBRKBJDI-UHFFFAOYSA-N Sevelamer hydrochloride Chemical compound Cl.NCC=C.ClCC1CO1 KHNXRSIBRKBJDI-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229920001688 coating polymer Polymers 0.000 description 1
- 238000012777 commercial manufacturing Methods 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 229940099371 diacetylated monoglycerides Drugs 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000005414 inactive ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000000905 isomalt Substances 0.000 description 1
- 235000010439 isomalt Nutrition 0.000 description 1
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000002475 laxative effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000011253 protective coating Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229960003027 sevelamer hydrochloride Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DESCRIPTION
[0001] The present invention relates to pharmaceutical compositions for oral administration comprising sevelamer carbonate, wherein the composition is free of crystalline cellulose, and (low-substituted) hydroxypropyl cellulose or other binding agents.
Background of the Invention [0002] Sevelamer is a non-absorbed phosphate binding polymer used in the treatment for the control of serum phosphorus in patients with Chronic Kidney Disease (CKD). Its chemical structure is as follows :
[0003] The compound contains multiple amines that become partially protonated in the intestine and interact with phosphate ions through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract facilitating phosphorus excretion in feces, Sevelamer lowers the plasma phosphorus concentration. The use of Sevelamer and its pharmaceutical compositions, and processes for its preparation are disclosed in EP 0716606, EP 0831857, EP 1133989 and EP 1676581.
[0004] Sevelamer may form acid addition salts. In existing medicinal products, Sevelamer is marketed, i.a., as Sevelamer carbonate (Renvela®). Renvela® contains microcrystalline cellulose, sodium chloride and zinc stearate as inactive ingredients. The tablets are coated with hypromellose and diacetylated monoglycerides.
[0005] According to the approved product information , sevelamer carbonate needs to be taken with meals. Therefore, rapid disintegration of a sevelamer carbonate containing tablet is conditional for phosphate binding efficacy, as it brings sevelamer in contact with food and allows binding of phosphate before it is absorbed by the intestinal tissue. Furthermore, the therapeutic dose is very high; the marketed tablets of sevelamer carbonate comprise 800 mg of the active substance per tablet and the daily dose may be up to 14 g per day.
[0006] Sevelamer carbonate is a compound of hygroscopic nature, wherein the adsorption of water is associated with serious changes in the volume. Sevelamer carbonate tablet cores
swell if uptake of moisture occurs. This can lead to rupture of the coating around the core, if the coating does not possess flexibility. Flexibility of the coating is particularly important for 'in-use' stability as patients might not always store the tablets according to the label recommendations.
[0007] Tablets comprising sevelamer, particularly sevelamer hydrochloride and sevelamer carbonate are known in the art.
[0008] WO 98/44933 and WO 00/22008 both describe tablets containing sevelamer, having an average particle size of 400 microns or less and 90% of the particles are less than 500 microns, together with crystalline cellulose (binder/diluent) and/or low-substituted hydroxypropyl cellulose (binder). The examples disclose 200 mg sevelamer compositions comprising 32.5% to 50.0% microcrystalline cellulose.
[0009] The applications further disclose that crystalline cellulose and low- substituted hydroxypropyl cellulose are desired to obtain a tablet disintegration time of less than 15 minutes, which is not obtained by using additives other than low- substituted hydroxypropyl cellulose or crystalline cellulose. The inventors describe in Example 1 (Table 1) the use of lactose and mannitol; however, no sufficient hardness (at least 6 KP) was reached.
[0010] The applications further describe a film-coated tablet wherein the film-coating may be made of water-soluble film bases such as hydroxypropylmethylcellulose and acrylic copolymers.
[0011] WO 01/28527 describes a tablet comprising a core and a coating wherein at least 95% by weight of the core comprises sevelamer. Further, the application describes water-based coatings for sevelamer tablets. The examples disclose the use of hydroxypropylmethylcellulose (HPMC) only.
[0012] WO 2006/050315 describes lactose amongst others as a suitable pharmaceutical carrier for sevelamer formulations, but provides no further information on the applicability.
[0013] WO 2008/062437 describes the use of mannitol as a preferred diluent in the range of 5% to 21% in combination with a binder added by a wet granulation process. Example 7 discloses the use of 10.8% mannitol in combination with ethyl cellulose (binder). The application describes that tablet compositions which use lactose as a diluent show discoloration as the tablets turn to yellowish brown color due to Maillard reaction.
[0014] Further, the application mentions several polymers for film coating. The coating may be used in the range of 3.0% to 8.0% by weight of total composition. The examples describe the use of a film coating aqueous process until a weight gain in the range of 4.0% to 6.0% is achieved (no specific film-coating polymer mentioned).
[0015] WO 2009/034540 describes compositions comprising sevelamer in an amount less than 80% by weight of composition. Furthermore, the application describes compositions comprising hydroxypropyl cellulose (HPC; binder), free of crystalline cellulose and low-substituted hydroxypropyl cellulose.
[0016] The examples disclose 400 mg sevelamer HCI compositions comprising 37.1% to 38.0% of diluent, lactose (Examples 1 and 2), mannitol (Example 10) and starch (Example 11). The examples disclose also 800 mg sevelamer compositions comprising 22% to 23.5% of lactose in combination with binder (Examples 3, 4, 5, 6, 13 and 14). Compositions comprising 15.5% to 16.5% mannitol in combination with binder are also disclosed (Examples 7, 8, and 9).
[0017] The application further mentions the use of film-forming polymers including Eudragit® or Opadry®, but provides no further information on applicability of such coating.
[0018] In all known 800 mg sevelamer carbonate formulations, binders are used, optionally in combination with a diluent, for developing a suitable sevelamer composition with an acceptable disintegration time. Although WO 2009/034540 disclosed the use of a diluent only, the amount of diluent used in the examples exceeds, however, the acceptable properties for an 800 mg sevelamer tablet.
[0019] Due to the high dose intake of sevelamer carbonate (800 mg per tablet), there is a need to develop an alternative composition of sevelamer carbonate with with low amounts of excipients and an acceptable disintegration time, which is easy to produce using direct compression manufacturing techniques.
[0020] Additionally, there is a need to develop an alternative composition of sevelamer carbonate with an acceptable disintegration time using a suitable flexible film-coating, wherein the coating is able to allow moisture uptake during shelf-life storage time and does not substantially increase the disintegration time of the sevelamer carbonate comprising tablets.
Summary of the Invention [0021] The present invention provides a pharmaceutical immediate release tablet comprising a core comprising 70-85 weight per cent of sevelamer carbonate, calculated as an anhydrous compound, 10-25 weight percent of lactose monohydrate and, optionally , a water soluble film coat surrounding the core.
[0022] Advantageously, the tablet comprises 800 mg of sevelamer carbonate.
[0023] Advantageously, the total mass of the tablet, inclusive the optional coating, does not exceed 1150 mg.
[0024] Advantageously, the film coat comprises polyvinyl alcohol-polyethylene glycol graft copolymer.
[0025] Advantageously, the amount of the film coat is 2-5 % of the weight of the tablet core.
[0026] Advantageously, the tablet does not comprise an added monovalent anion source and/or a disintegrant and/or a surfactant.
[0027] Advantageously the tablet has a hardness of about 150 N and higher and/or has a disintegration of less than 10 minutes using a conventional tablet disintegration apparatus (Pharmatest) in accordance with the European Pharmacopoeia (Ph.Eur 2.9.1) in purified water without using the disk.
[0028] In a second aspect, the invention provides a process for making immediate release tablets comprising sevelamer carbonate , said process comprising tabletting, by a direct compression, a dry mixture of 70-85 weight per cent of sevelamer carbonate, calculated as an anhydrous compound, 10-25 weight percent of monohydrate of lactose and .optionally .other excipients.
[0029] Optionally, the tabletting step is followed by a step of coating the formed tablets by a water soluble film coat; advantageously the coat comprises polyvinyl alcohol-polyethylene glycol graft copolymer.
[0030] In further aspects, the invention relates to the use of tablets according to the invention as medicaments for the control and/or adjustment of the level of serum phosphorus, and to the use of polyvinyl alcohol-polyethylene glycol graft copolymer for making coated tablets comprising sevelamer, particularly sevelamer carbonate.
Detailed description of the invention [0031] The objective of the invention is to provide directly compressible film-coated tablets comprising sevelamer carbonate with short disintegration time, high drug load, and sufficient hardness. Furthermore, another object of the invention was to provide a suitable film-coating material protecting the hygroscopic tablet core comprising sevelamer carbonate but not affecting the overall release of the drug.
[0032] Due to hygroscopic nature of sevelamer carbonate associated with serious volume gain during the uptake of water, the useful tabletting procedures are limited to direct compression, dry granulation and non-aqueous wet granulation. The non-aqueous wet granulation (a granulation using organic solvents, e.g. alcohols) is laborious, not applicable in many pharmaceutical plants, more expensive, and environment-unfriendly. Therefore, the aim of the research was to provide a composition of the tablet core that was tablettable by a dry process, preferably by the direct compression and most preferably by a direct compression without any wetting step.
[0033] Due to the therapeutical dose of sevelamer carbonate, which requires to make the final tablets comprising 800 mg of the active, the resulting tablet is generally very big. It is commonly accepted that tablets having the total weight of 1000-1100 mg are still swallowable, except, of course, for disabled patients. Therefore, the aim of the research was to provide a composition having at least 70 %, preferably between 70 and 85 weight % of the sevelamer carbonate (calculated as an anhydrous compound) in the core, in other words, a composition having, in total, only 15-30 % of other excipients. The "other excipients" also include water , which is present in the composition and originates both from the active substance (the active substance may inherently contain up to 8 % of water) and from the excipients and environment; even when a dry tabletting process is used, some water may be adsorbed into the composition from the environment. In average, the overall content of water in the composition is generally about 3 %.
[0034] The role of excipients in the immediate release tablet comprising 70-85 % of sevelamer carbonate is generally to bind the composition in the tabletting process into a sufficiently hard and stable tablet and, on the other hand, to allow sufficiently rapid disintegration of the tablet matrix in the stomach environment. It was proven that it is impossible to obtain a tablet with sufficient hardness and disintegration just by tabletting sevelamer carbonate without any binding excipients.
[0035] In the key aspect, various water soluble diluents and disintegrant excipients suitable for direct compression tabletting process were tested in respect to the final disintegration time with the goal to provide a stable hard tablet comprising from 70 to 85 % of sevelamer carbonate , preferably comprising 800 mg of the active compound , calculated as an anhydrous substance, within a tablet having the overall mass of about 1100 mg, whereby the produced tablet may have exhibit the disintegration time of less than 10 minutes, when measured according to Ph.Eur. standard disintegration test (Art. 2.9.1) in purified water without using the disk. The experimental arrangements and results of the corresponding tests are provided in Experimental Example A below. 1. a) In respect to the tested excipients, it was found that lactose monohydrate, mannitol and the mixtures of microcrystalline cellulose with silicified cellulose provide the tablets having the shortest disintegration times. Only with these three excipients, the required tablet disintegration times of < 10 minutes were obtained. The use of many other excipients - such as anhydrous lactose, povidone, co-povidone, HPC with low viscosity, compressible sugar, isomalt and starch-lead to substantially longer disintegration times (> 10 minutes). No explanation was found for this surprising result. It was expected that the use of any well soluble excipient and /or swelling excipient would lead to short tablet disintegration time. However, in the case of high loaded sevelamer carbonate formulation, many excipients known for high solubility and/or swelling capacity did not lead to short tablet disintegration time, except for lactose monohydrate, mannitol and cellulose/silicified cellulose mixtures. A relation between the binding strength of the excipients and the disintegration time might have been expected, but also this relation was not found.
[0036] Among these suitable excipients, the lactose monohydrate has the best disintegration properties in the sevelamer carbonate tablet compositions. It provides the sevelamer carbonate tablets with sufficient hardness and smooth surface, i.e. well suitable for the subsequent film-coating. Furthermore, mannitol, like many other polyols, is not a suitable excipient for tablets that should be used by patients with kidney diseases in high doses. Laxative effects of mannitol are more pronounced with kidney disease patients due to the limited water intake associated with dialysis, and absorbed mannitol exerts uncontrolled diuretic effect on the kidneys. Accordingly , lactose monohydrate , in an amount of 10-25 % and most preferably 20-25 % of the tablet composition, is the most suitable excipient for making a high loaded immediate release tablet comprising sevelamer carbonate. Both the spray- dried and the granulated lactose monohydrate are suitable in the invented tablets.
[0037] Contrary to certain prejudice, the presence of lactose monohydrate in the composition does not affect the stability of the phosphate binding capacity. Sevelamer is the molecule that comprises a large extent of primary amino groups. Lactose is a component that is generally known for its reactivity with primary amino groups by a Maillard-type condensation reaction. The handbooks state that lactose and primary amines are generally incompatible. The reaction of lactose with the primary amine groups of Sevelamer would reduce the phosphate binding capacity, as the intact primary amino groups are essential for the phosphate binding functionality of sevelamer. However, surprisingly, the phosphate binding capacity of the tested tablets remained stable as shown in the Example B . Furthermore, no colourisation to brown or yellow-brown colour due to a Maillard-type reaction was observed.
[0038] The above tablet composition of sevelamer carbonate with lactose monohydrate also exhibits good stability of the disintegration time. While WO 2006/050315 indicates that the disintegration time of Sevelamer carbonate tablets increases with time of storage if no monovalent anion source was added in tablets and the marketed Renvela product contains the added sodium chloride according to the label, the composition of the present invention, however, does not comprise any added monovalent anion source and still the composition exhibits a stable disintegration time. b) Use of disintegrants (crospovidone, sodium starch glycolate) was investigated with the aim to shorten the disintegration time of high-loaded sevelamer carbonate tablets. It was found with surprise that disintegrants did not shorten the disintegration time substantially. Sometimes, formulations with disintegrants showed actually slightly shorter disintegration time than comparable formulations without disintegrants, but, on the other hand, the hardness of the so produced tablets decreased to undesired levels due to compaction inhibiting properties of the disintegrants.
[0039] In case of starch, a filler known for swelling and tablet disintegrating properties, it was found that the disintegration time actually increased.
[0040] Therefore, the composition of the present invention preferably does not comprise any excipient that may serve as a disintegrant. c) Use of a surfactant (sodium lauryl sulphate), which can improve the disintegration time sometimes, did not lead to shorter disintegration time either. Therefore, no surfactant is used in the composition of the invention. d) Lastly, an excipient that may serve as a lubricant may be added into a composition. The lubricant improves tabletting properties of the composition and limits the adhesion of the composition to the tablet press. Suitable lubricant is, e.g., zinc stearate, magnesium stearate or stearic acid. The suitable amount of the lubricant is from 0.5 to 1.0 weight %.
[0041] The present invention also provides a process for making immediate release tablets comprising sevelamer carbonate, said process comprising tabletting, by a direct compression, a dry mixture of 70-85 weight per cent of sevelamer carbonate, calculated as an anhydrous compound, 10-25 weight percent of monohydrate of lactose and .optionally, other excipients. The direct compression tabletting process comprises homogenization of the dry components in a suitable homogenizer and tabletting the homogeneous mixture in a tablet press under suitable tabletting pressure. The tabletting pressure may be adjusted to obtain preferably a tablet with a hardness of about 150 N and higher.
[0042] In particular, the process does not comprise any wetting step regardless the fact that wetting of sevelamer is sometimes recommended in the literature. Mostly, passive wetting by uptake of atmospheric moisture has been described to improve compactibility. This method is difficult to control and hardly applicable for commercial manufacturing with bulk quantities. Wetting of sevelamer by addition of water to a high shear mixer has also been described. This process requires considerable storage time for water equilibration after spraying and an additional milling step to get rid of lumps. Also it was found experimentally that sevelamer carbonate tends to form elastic lumps upon contact with water that could only be milled with conventional milling equipment upon hardening of the lumps after considerable storage time. Therefore, a direct compression process that does not require a wetting step is preferred.
[0043] The sevelamer carbonate tablets of the present invention are preferably film-coated to improve the handling properties and, particularly, to minimize the water uptake into the tablet during storage. Inherently, sevelamer carbonate tablet cores swell if the uptake of moisture occurs. Hence, a flexible protective coating is desired for high-loaded sevelamer carbonate tablets. Flexibility of the coating is particularly important for 'in-use' stability as patients might not always store the tablets according to the label recommendations.
[0044] In the second condition, the film coat should not increase the overall disintegration time in purified water. The film coat material should therefore be well soluble in water.
[0045] Three comparably soluble flexible coatings were evaluated experimentally for use with sevelamer carbonate tablet cores. Surprisingly it was found that use of polyvinyl alcohol-polyethylene glycol graft copolymer results in the lowest disintegration time of the overall composition. No explanation has been found for this observation.
[0046] The coating comprising polyvinyl alcohol-polyethylene glycol graft copolymer is commercially available under trade name Kollicoat IR by BASF. Apart of polyvinyl alcohol-polyethylene glycol graft copolymer, the coating material may comprise also other excipients improving the appearance and processability, such as colourants (e.g. titanium dioxide), antitacking agents (e.g. talc, kaolin) and glidants (e.g. silicon dioxide).
[0047] The advantage of the Kollicoat -type coatings over the most commonly used coatings based on polyvinylalcohol (PVA) and hypromellose (HPMC) was demonstrated by comparing the gains of the disintegration time (measured according to Ph.Eur. 2.9.1. in purified water without using the disk) after coating the tablet core prepared according to the invention with 3 % of the respective coatings (see Example C). While the PVA- and HPMC- type coating increases the disintegration time by about 5-10 minutes, the same amount of the Kollicoat coating increases the disintegration time by about 2 minutes only.
[0048] Accordingly, suitable film-coated high-loaded tablets comprising sevelamer carbonate and lactose monohydrate advantageously comprise 2-10 % , preferably about 2.5-5 % and most preferably about 3 % of the coating comprising polyvinyl alcohol-polyethylene glycol graft copolymer.
[0049] The tablet cores may be coated by a standard coating process by spraying a water suspension of the coating material at the set temperature in a coating equipment, e.g. in a conventional drum coater, until the desired weight gain is obtained. Kollicoat IR can be used for coating in a broader temperature range (15-50°C) than HPMC and PVA coatings, particularly at lower temperatures. Coating at low temperatures saves energy and improves the uniformity of the coating. Kollicoat IR has relatively low viscosity and can therefore be used for coating fluids with high solid content (15-25% polymer concentration and 20-35% overall solids with pigments). The high solid content reduces processing time in the manufacture of film-coated tablets. Accordingly, it can be concluded that the use of polyvinyl alcohol-polyethylene glycol graft copolymer, e.g. Kollicoat IR, for making coated tablets comprising sevelamer, particularly cevelamer carbonate, which use is one of the aspects of the present invention, is advantageous not only from the point of coating properties but also from technological aspects.
[0050] The tablets of the present invention are useful as a medicament for the control and/or adjustment of the level of serum phosphorus, particularly in patients with Chronic Kidney Disease (CKD). The phosphate binding capacity is comparable with that of the pure active ingredient and with the currently marketed sevelamer carbonate drug product (Renvela).
[0051] The results of experiments showing the superiority of the compositions and tablets of the present invention are summarized in the following Examples .
EXAMPLES
Example A (not according to the invention): Comparison of tablet core formulations [0052] Tablets core formulations were compared with regard to disintegration time. To enable scientifically sound comparison of the various formulations, blends were prepared according to the same procedure and compacting was done with the same equipment, equipment settings, tooling and compression force.
[0053] Tablets were prepared according to the following procedure:
Sevelamer and colloidal silicon dioxide were blended (Turbula blender, 5 min) and screened. Remaining excipients - except lubricant - were added and blended (15 minutes). Lubricant was added for final blending (5 min). Blend was compressed with 30 kN compression force using excenterpress (Korsch EK-0) equipped with 10x19 mm oblong shaped tooling.
[0054] Disintegration time of tablets was determined by using a conventional tablet disintegration apparatus (Pharmatest) in accordance with the European Pharmacopoeia (Ph.Eur 2.9.1) in purified water without using the disk.
Table A Formulations based on MCC, starch and disintegrants (amounts in milligram per tablet)
Table B Formulations based on various soluble binders (1) (amounts in milligram per tablet)
* 800 mg anhydrous Sevelamer after water content correction of 4.5%
Table C Formulations based on various soluble binders (2) (amounts in milligram per tablet)
* 800 mg anhydrous Sevelamer after water content correction of 4.5%
Table D Formulations based on lactose (amounts in milligram per tablet)
* 800 mg anhydrous Sevelamer after water content correction of 4.5%
Table E Formulation with surfactant (amounts in milligram per tablet)
* 800 mg anhydrous Sevelamer after water content correction of 4.5%
Example B (not according to the invention): Stability of phosphate binding capacity and disintegration time of lactose formulation [0055] The phosphate binding capacity and disintegration time of Sevelamer tablets with
lactose as binder were found to be stable. Stability studies were performed in accelerated conditions (40°C/75%RH) and stress conditions (55790%).
Tablets of stability studies (amounts in milligram per tablet)
* 800 mg anhydrous Sevelamer after water content correction of 4.5% [0056] The tablets were packed in regular HPDE containers. The phosphate binding remained unchanged and the disintegration time decreased slightly.
Stability of disintegration time (minutes) [0057]
Stability of phosphate binding capacity (mmol PO^g SVL) [0058]
Example C (not according to the invention): Coating of lactose-based tablets with PVA-based coating, with Kollicoat IR based coating, and with HPMC based coating [0059] Tablets were prepared on equipment suitable for industrial manufacturing according to the following procedure:
Sevelamer carbonate and colloidal silicon dioxide were blended (Bohle free-fall blender, 5 min) and screened. Remaining excipients - except lubricant - were added and blended (15 minutes). Lubricant was added for final blending (5 min). Blend was compressed with rotary press (Korsch PH106) equipped with 11x18.5 mm oblong shaped tooling.
[0060] The tablet cores were coated to a weight gain of 3% in a conventional drum coater (Bohle BLC5) at a product temperature of ± 45°C for the PVA-based coating, at ± 30°C and ± 42°C for the Kollicoat IR based coating and at ±42°C for the HPMC based coating.
[0061] Disintegration time of tablets was determined by using a conventional tablet disintegration apparatus in accordance with the European Pharmacopoeia (Ph.Eur 2.9.1) in purified water without using the disk.
Tablet formulations of comparative coating trials (amounts in milligram per tablet)
* 800 mg anhydrous Sevelamer after water content correction of 4.5% 1 containing: polyvinyl alcohol, titanium dioxide, polyethyleneglycol, talc
[0062] A substantial increase of disintegration time was seen with PVA-based coating and with HPMC-based coating. A smaller increase of disintegration time was seen with Kollicoat IR
based coating:
Disintegration time of lactose-based tablets before and after coating [0063]
Example 1 - Tablet cores: Ό064] Composition (amounts in miligrams per tablet) :
* corresponds to 800 mg anhydrous Sevelamer carbonate after water content^ correction of 4.5%
Process: [0065] Sevelamer carbonate and colloidal silicon dioxide were blended (Turbula blender, 5 min) and screened. Lactose monohydrate was added and blended (15 minutes). Lubricant was added for final blending (5 min). Blend was compressed with 30 kN compression force using excenterpress (Korsch EK-0) equipped with 10x19 mm oblong shaped tooling.
[0066] Disintegration time according to the Ph.Eur. 2.9.1. in purified water without using the disk: less than 10 minutes
Example 2 - Coated tablets [0067] Composition (amounts in miligrams per tablet) :
* corresponds to 800 mg anhydrous Sevelamer carbonate after water content^ correction of 4.5%
Process : [0068] The tablet cores prepared according to the formulation of the example 1 were coated to a weight gain of 3% in a conventional drum coater (Bohle BLC5) at a product temperature of ± 30°C by the Kollicoat IR based coating.
[0069] The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description • EP0716606A [00031 • EP0831857A [0003] • EP1133989A [00031 • EP1676581A [0003] • WO9844933A [0008] • W00022008A [0068]
• WOQ128527A [00111 • WQ200605Q315A [00121 [00381 • WQ2008062437A [00131 • WQ20Q903454QA [001 Sj [0018]
Claims (12)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/EP2009/007586 WO2011047700A1 (en) | 2009-10-22 | 2009-10-22 | Pharmaceutical compositions of sevelamer |
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| Publication Number | Publication Date |
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| DK2490675T3 true DK2490675T3 (en) | 2019-04-29 |
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| DK09741235.7T DK2490675T3 (en) | 2009-10-22 | 2009-10-22 | Pharmaceutical compositions with sevelamer |
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| US (1) | US20120219626A1 (en) |
| EP (1) | EP2490675B1 (en) |
| DK (1) | DK2490675T3 (en) |
| EA (1) | EA024699B1 (en) |
| ES (1) | ES2720869T3 (en) |
| WO (1) | WO2011047700A1 (en) |
| ZA (1) | ZA201203719B (en) |
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| US20100330175A1 (en) * | 2009-06-24 | 2010-12-30 | Jobdevairakkam Christopher N | Cross-linked polyallylamine tablet core |
| JP6453860B2 (en) | 2013-06-05 | 2019-01-16 | トリシダ・インコーポレイテッドＴｒｉｃｉｄａ， Ｉｎｃ． | Proton-bonded polymer for oral administration |
| ME03783B (en) | 2014-12-10 | 2021-04-20 | Tricida Inc | PROTONS BINDING PROTONS FOR ORAL APPLICATION |
| US20180015119A1 (en) * | 2015-02-23 | 2018-01-18 | Amneal Pharmaceuticals Company Gmbh | Process for granulating sevelamer carbonate |
| MA44875A (en) | 2016-05-06 | 2019-03-13 | Tricida Inc | COMPOSITIONS FOR THE TREATMENT OF ACID BASIC DISORDERS |
| EP3703706A4 (en) | 2017-11-03 | 2022-04-27 | Tricida Inc. | COMPOSITIONS AND METHOD FOR TREATING ACID-BASE DISORDERS |
| CN110664772A (en) * | 2019-09-27 | 2020-01-10 | 方达医药技术（苏州）有限公司 | Sevelamer carbonate tablet and preparation method thereof |
| CN111773190A (en) * | 2020-06-24 | 2020-10-16 | 北京瑞迪道森医药科技有限公司 | Sevelamer carbonate tablet for improving safety of preparation and preparation method thereof |
| CN112220762B (en) * | 2020-09-07 | 2022-08-19 | 湖北华世通生物医药科技有限公司 | Sevelamer carbonate coated tablet and preparation method thereof |
| CN116549409A (en) * | 2022-01-27 | 2023-08-08 | 湖北华世通生物医药科技有限公司 | Sevelamer carbonate coated tablet and preparation method thereof |
| KR102891050B1 (en) * | 2023-12-27 | 2025-11-25 | 주식회사 대웅제약 | Pharmaceutical formulation comprising sevelamer or pharmaceutically acceptable salt, and preparation method thereof |
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| TW592727B (en) * | 1997-04-04 | 2004-06-21 | Chugai Pharmaceutical Co Ltd | Phosphate-binding polymer preparations |
| HK1049451B (en) * | 1999-10-19 | 2005-12-16 | Genzyme Corporation | Direct compression polymer tablet core |
| DE102005024614A1 (en) * | 2005-05-25 | 2006-11-30 | Röhm Gmbh | Use of polymer blends for the production of coated drug forms and drug form with polymeric blend coating |
| CN101404982A (en) * | 2006-02-14 | 2009-04-08 | 特瓦制药工业有限公司 | Pharmaceutical formulation of aliphatic amine polymer and their preparation method |
| WO2009034540A1 (en) * | 2007-09-11 | 2009-03-19 | Ranbaxy Laboratories Limited | Pharmaceutical composition of sevelamer |
| DE102008030046A1 (en) * | 2008-06-25 | 2009-12-31 | Ratiopharm Gmbh | Preparation of tablets comprising polyallylamine polymer, useful for treating e.g. hyperphosphatemia, comprises mixing polyallylamine polymer and additives, compacting to slug, granulating the slug and compressing the granules into tablets |
| US20100008988A1 (en) * | 2008-07-14 | 2010-01-14 | Glenmark Generics, Ltd. | Tablet compositions of amine polymers |
-
2009
- 2009-10-22 DK DK09741235.7T patent/DK2490675T3/en active
- 2009-10-22 EP EP09741235.7A patent/EP2490675B1/en active Active
- 2009-10-22 WO PCT/EP2009/007586 patent/WO2011047700A1/en not_active Ceased
- 2009-10-22 US US13/503,643 patent/US20120219626A1/en not_active Abandoned
- 2009-10-22 EA EA201270581A patent/EA024699B1/en not_active IP Right Cessation
- 2009-10-22 ES ES09741235T patent/ES2720869T3/en active Active
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| EA201270581A1 (en) | 2012-12-28 |
| EP2490675B1 (en) | 2019-01-23 |
| EA024699B1 (en) | 2016-10-31 |
| US20120219626A1 (en) | 2012-08-30 |
| EP2490675A1 (en) | 2012-08-29 |
| WO2011047700A1 (en) | 2011-04-28 |
| ZA201203719B (en) | 2013-08-28 |
| ES2720869T3 (en) | 2019-07-25 |
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